Neonatal jaundice occurs in 60-70% of all newborn infants. It is caused not only by an overproduction of bilirubin, but also by a transient failure to excrete this metabolite. Hyperbilirubinemia is exacerbated by hemolytic diseases, such as Rhesus isoimmunization and ABO incompatibility, which result in increased bilirubin production, as well as diseases that result in decreased bilirubin excretion. The rate-limiting enzyme in the production of bilirubin is heme oxygenase (HO), and as such is a key therapeutic target. Inhibition of HO activity has been shown to protect newborns from excessive hyperbilirubinemia. Heme analogs, metalloporphyrins (Mps), are potent competitive inhibitors of HO enzyme activity. The use of Mps as oral therapeutic agents may be an effective approach for the prevention and treatment of hyperbilirubinemia. In this proposal, we will extend our preliminary studies of chromium mesoporphyrin (CrMP), which is a potent HO inhibitor, absorbable orally and photo-inert, in the newborn mouse. In anticipation of positive findings, we propose to extend these studies further to the non-human primate newborn model. In our laboratory, we have continued to develop and validate assays to monitor in vivo heme degradation and HO-1 transcriptional patterns and in vitro enzymatic activity of HO so that we can evaluate regulation and expression at these two levels. Application of these approaches to the neonatal mouse model is a natural extension of our work with the newborn rat, mouse, and monkey models. The results of this project will assist in the design of future clinical studies of CrMP by providing both spatial and temporal information pertaining to its direct effects on the enzymatic target, its expression, and subsequent short- and long-term effects on the newborn animal. The specific aims of this application are directed at evaluating the efficacy and safety of CrMP for the treatment of neonatal jaundice through inhibition of HO activity and serves as a basis for a "pre-clinical" IND evaluation of its potential efficacy and safety for use in the human neonate, with particular emphasis on short- and long-term effects in the heme-loaded newborn mouse. Use of a newborn mouse model should permit well-controlled systematic studies preceding the administration of CrMP, a very promising inhibitor, for the treatment of neonatal jaundice. PUBLIC HEALTH RELEVANCE: Heme oxygenase (HO) is a key therapeutic target in the prevention of neonatal jaundice. We have been investigating the efficacy and safety of metalloporphyrins (Mps) for their potential use in the treatment of neonatal jaundice. In this proposal, we propose to extend our studies of CrMP in the mouse because CrMP is a potent HO inhibitor, absorbable orally and photo-inert. The specific aims of this application serve as a basis for a "pre-clinical" IND evaluation of potential efficacy and safety of CrMP for use in the human neonate, with particular emphasis on short- and long-term effects in the heme-loaded newborn mouse.